Man with flies and snake, crayon drawing from the 1920s by Heinrich Anton Müller, an artist and inventor who spent much of his life in a Swiss psychiatric hospital under treatment for delusions and other symptoms of schizophrenia.

Courtesy of the Collection de l’Art Brut, Lausanne, Switzerland

Just one glance at a painting by a person with schizophrenia clues you in. This person, you think, is not your run-of-the-mill artist. This artist has something going on.

What’s going on in the mind of a person with schizophrenia has been the subject of researchers for nearly a century. Some believe that the divergent thought processes at the heart of creativity are cousin to the delusions and hallucinations that characterize the disorder. Other, more fundamental thought processes are affected in schizophrenia, too, including some essential to navigating daily life. Surprisingly, perhaps, it is largely this cognitive impairment that prevents those with the disorder from participating in society.

Affecting around one percent of the population worldwide, schizophrenia does not discriminate by race, socioeconomic status, or intelligence. The illness typically surfaces in early adulthood, and may impact a person’s ability to think clearly, manage emotions, and interact with others. Most people with the disorder suffer chronically or episodically throughout their lives, plagued by symptoms and medication side effects, as well as by stigma and the pain of lost opportunities for relationships and careers. One of every 10 people with schizophrenia eventually commits suicide.

Though its cause is still uncertain, most scientists in the field agree that schizophrenia is a problem with brain growth and development. Technological advances in neuroscience, genetics, and brain imaging are yielding convincing evidence of altered brain anatomy and chemistry.

Yet the picture of when and how neurological snarls occur remains vague: Is nascent brain circuitry affected in the womb or some time later along the developmental timeline? Genes are involved, but is the initiating event biological or environmental?

Of a split mind

Our understanding of schizophrenia has come a long way since German psychiatrist Emil Kraepelin first documented the disorder in the late 1800s. The symptoms are by now well characterized, yet misconceptions still abound. The Greek-derived name translates to “split mind,” but the illness has nothing to do with split or multiple personality disorders. The “split” in this case refers to the inability to separate reality from delusion and the illogical from the reasonable.

A wide-ranging array of symptoms characterizes the illness, which profoundly disrupts cognition and emotion, affecting language, thought, perception, affect, and sense of self. Diagnosis encompasses a pattern of signs and symptoms—often including psychotic symptoms, such as hearing imagined voices or espousing false yet fervent personal beliefs—in conjunction with an impaired ability to participate socially or occupationally.

Schizophrenia can occur at any age, but it tends to first become evident between adolescence and young adulthood, somewhat earlier in men than in women but at about the same rate. Retrospective studies reveal signs of cognitive decline—a slide in grades or withdrawal from friends and family, for example—well before the first psychotic “break.” The conditions necessary to produce such neurological havoc remain an enigma.

“That’s why it’s so difficult,” says Pat R. Levitt, Ph.D., director of the Vanderbilt Kennedy Center for Research on Human Development. “It’s a disorder that is complicated because it affects two major mental domains, because it is clearly multi-genic, and because it also has environmental contributors. And yet, out of all the psychiatric disorders that people work on, other than depression, it is the most prominent, affecting one in 100 people.”

It has long been accepted that schizophrenia has a genetic component. The risk for inheriting the disorder is 10 percent in those who have one immediate, or first-degree, family member affected, and about 40 percent if the illness is shared by both parents or by an identical twin.

It’s important to note, however, that the majority of people with schizophrenia have no close relatives who are affected, an indication that there are other factors at play. Epidemiological evidence suggests certain external circumstances, such as viral infection during pregnancy, insufficient prenatal nutrition, or a child’s being born during the winter months or being born in an urban setting, may increase risk.

“This is not to say that you have a higher risk being born in a city hospital rather than in the country,” says Levitt. “It’s probably related to some increased incidence of something a mother is exposed to—infection or perinatal stress, for example—if pregnancy occurs in these different environments.”

Stilling the tempest

Sorting out which behaviors in schizophrenia are linked to genetic changes in the brain, and how those changes impact neurological chemistry and circuitry, has proved challenging. One of the first clues about altered brain chemistry in schizophrenia came in the early 1950s with the introduction of the antipsychotic drug chlorpromazine (trade name Thorazine). Originally used as an antihistamine during surgical procedures, the drug’s sedative properties inspired a psychiatrist to try it on agitated institutionalized mental patients.

Dr. Herbert Y. Meltzer, who has helped pioneer the development of "atypical" antipsychotic drugs at Vanderbilt, is using positron emission tomography (picutred here) to study the effect of these medications on cognitive function in patients with schizophrenia.

To everyone’s surprise, the drug not only sedated, it also diminished delusions and hallucinations. As doctors pushed the dose, however, patients developed Parkinson’s-like conditions: rigidity, loss of movement, drooling. The story led Swedish scientist Arvid Carlsson, who would later win a Nobel Prize for his work, to discover dopamine and its role as a neurotransmitter in communicating instructions between the brain’s nerve cells.

Studies showed that many antipsychotic agents block dopamine receptors, suggesting that an excess of dopamine in the brain may be part of schizophrenia’s pathophysiology. Dopamine’s role in schizophrenia dominated the field for some time, and though other neurotransmitters—glutamate, GABA, acetylcholine, and serotonin, for example—have since been implicated in the disease process, the “dopamine hypothesis” continues to be a central focus.

“The evidence is that multiple brain chemical systems all come to bear on the synthesis, release, and inactivation of dopamine in various areas of the brain — too much in some, too little in others,” says Dr. Herbert Y. Meltzer, Bixler/Johnson/Mays Professor of Psychiatry and director of the Division of Psychopharmacology at Vanderbilt.

“It’s like the ‘six degrees of separation’ concept,” he says. “You might start over here with glutamate or GABA, but sooner or later it’s going to link up with dopamine as a key element in the final common pathway of the disordered brain function.”

Meltzer has a history of contributions to the field of schizophrenia drug development, beginning with his efforts showing that clozapine—the first of the second-generation “atypical” antipsychotic drugs—effectively treats psychosis without producing Parkinsonism. Late last year, the FDA named clozapine the drug of choice to reduce suicidal behavior in schizophrenia, an endorsement due in large part to an international clinical trial led by Meltzer.

Using functional PET (positron emission tomography), a brain scanning technique, Meltzer and Dr. Robert M. Kessler, professor of Radiology and Radiological Sciences at Vanderbilt, have found that clozapine-like drugs produce a different pattern of dopamine receptor blockade in cortical and limbic (“emotional brain”) areas. This finding provides evidence that the delusions and hallucinations may be the result of excessive dopamine in the limbic system, while the cognitive impairment may be due, in part, to too little dopamine in the cortex, he says.

During the course of his studies with clozapine, Meltzer and his colleagues found that the drug improved some elements of cognitive function in schizophrenia patients. Confirmation of this first evidence that an antipsychotic drug could improve cognitive impairment changed the focus of the search for better drugs for schizophrenia, making cognition a primary and separate target.

Meltzer’s current research is designed to identify new treatments to further improve cognitive impairment in schizophrenia. Success, he believes, may lead to drugs to treat many forms of cognitive loss, including those due to aging and Alzheimer’s disease.

A shift in focus

A look inside the brains of schizophrenia patients shows that the structure is not dramatically changed by the illness. One subtle change is the decreased size of the frontal lobe in schizophrenia patients. Since the frontal lobe is the seat of many of the brain’s higher cognitive functions, it’s been a logical destination for schizophrenia researchers in search of aberrations, including Sohee Park, Ph.D., professor of Psychology and Psychiatry at Vanderbilt.

Park’s work draws on the contributions of the late Patricia Goldman-Rakic, Ph.D., a Yale University neuroscientist who pioneered current understanding of memory function and was the first to describe the order and structure of the frontal lobe.

When Park was working on her doctorate, Goldman-Rakic reported that monkeys with lesions in the frontal lobe were bad at tasks that required spatial working memory—the ability to remember the location of an object after a brief delay.

Park adapted Goldman-Rakic’s work in the primate model, designing a spatial working memory test for humans.

Park used the test to study performance of schizophrenia patients versus normal individuals and patients with bipolar disorder, and found that only those with schizophrenia had problems with the task. She expanded her studies to people with schizotypal personality disorder, or schizotypy, a milder version of schizophrenia often seen in first-degree relatives.

“As might be predicted,” Park says, “the performance of people with schizotypy falls in-between that of normal controls and people with the full-blown disorder.”

Monitoring the brains of those performing the task using a special scanning technique called functional magnetic resonance imaging, or fMRI, Park found that normal individuals have increased activity in a specific region of the frontal lobe—the convex shaped area on either side of the head, just above the temple, known as the dorso-lateral prefrontal cortex.

Results in schizophrenia patients are very different. “In those with schizophrenia, you don’t see increased activity in this part of the brain and you see a higher error rate,” says Park. “But they don’t get all the answers wrong, so it’s not that the area isn’t functioning at all.”

In some studies, even when patients got the right answer, this part of the brain wasn’t activated. This suggests that they don’t seem to need that area to perform the task correctly, she adds.

“So the fMRI literature is in some sense murky right now, because we don’t know what the activation really means in normal individuals versus schizophrenia patients,” says Park. “Overall, it gives the idea that something is wrong with the way they use the brain, though we don’t know yet exactly how.”

Park is collaborating with Meltzer, using fMRI to look at how working memory is affected in schizophrenia patients treated with both an atypical antipsychotic and the drug buspirone, which specifically targets the brain’s serotonin system. In addition, she is exploring the use of other brain imaging technologies with the help of John C. Gore, Ph.D., director of Vanderbilt’s Institute of Imaging Science, and his colleagues.

Park expects that one method, near infrared optical imaging, may prove particularly helpful, since it provides the same kind of information that fMRI does, but has the advantage of allowing the patient to sit up and move more freely while being tested.

Neural circuitry and its genetics

Dr. David A. Lewis has spent years studying neural circuitry in the brain, specifically the prefrontal cortex and related brain regions, and how it is altered in schizophrenia. It was at the University of Pittsburgh where he is director of the Center for the Neuroscience of Mental Disorders, and where Levitt was chairman of the department of Neurobiology at the time, that the two first began their collaborative research into the genetic underpinnings of those alterations.

“David and I partnered with Karoly Mirnics, who was an M.D. neurophysiologist in my lab, and who was also fantastic with computers and data analysis,” Levitt recalls. “We were the first group to use gene microarrays applied to a major brain disorder, and we focused on the dorso-lateral prefrontal cortex, the area that mediates working memory, which is disturbed in schizophrenia.”

Gene microarray studies allow for simultaneous screening of thousands of genes to look for patterns of gene expression. The Pittsburgh group has published a series of papers demonstrating that expression of a certain class of genes—those encoding proteins that control synapse function—is deficient in schizophrenia. Some of these proteins have other roles in the body, but in the brain they play a critical role in the modulation of how neurons communicate with one another.

“We found that in one of those genes, rgs4, there are some polymorphisms — differences in gene sequences—that are found more prominently in people with schizophrenia than those without,” says Levitt. “What we’re trying to do now is to figure out whether the changes we see in our microarray studies are primary to the disorder or whether they actually reflect an adaptive state—an attempt by neurons to compensate for the principal defect.”

“What’s been striking to us is that the components of the prefrontal cortex that we knew were likely to be important for working memory activity appear to be those that are preferentially disturbed,” adds Lewis. “And other components, which seem to be playing different roles in the prefrontal cortex, are relatively preserved.”

Studies of brain tissue from schizophrenia patients show fewer neurons extending into the prefrontal cortex from the thalamus, a brain region that serves as a processing center for sensory impulses. In addition, communication among neurons is impaired, due to reduced synaptic connections and a lower density of dendritic spines, the nubs on neuronal cell bodies whose job it is to receive thalamic input.

Lewis’ lab has discovered further surprising detail about the prefrontal cortex neurons: A subset that connects with a distinct population of inhibitory neurons has an altered receptor for GABA, the major inhibitory neurotransmitter in the brain. Lewis is designing a clinical trial to evaluate a new drug targeted at this altered receptor.

“To me, what is exciting is to start with very basic science—how the prefrontal cortex normally mediates working memory—then to go to the illness and ask what’s wrong with that circuitry, and in the context of that find an alteration that might be druggable,” he says. “We’ll see in the initial clinical trial whether there’s any evidence of cognitive improvement.”

Translational research

This kind of systematic application of scientific method to the goal of drug discovery is an important aspect of what is called translational research, and it’s the bailiwick of P. Jeffrey Conn, Ph.D., professor of Pharmacology and director of the Vanderbilt Program in Drug Discovery. Conn, who earned his doctorate in Pharmacology at Vanderbilt, was recruited in 2003 from Merck & Co., Inc., where he headed the company’s schizophrenia drug development efforts.

Conn has been investigating the role of the neurotransmitter glutamate in schizophrenia. Glutamate is the “major workhorse in the brain, affecting virtually every circuit involved in any brain function,” he says. Unfortunately, it’s that broad functioning that makes the neurotransmitter such a difficult drug target — effects of a drug would be seen throughout the central nervous system. So when a new class of glutamate receptors, called the metabotropic glutamate (mGlu) receptors, was discovered, a door to more specific control opened.

“The evidence suggested that they could fine-tune activity in glutamate circuits,” Conn explains. “So instead of hitting the circuit with a sledgehammer, it’s a subtle modulation of activity in that circuit.”

Because mGlu receptors are located on both sides of the synapse, they are involved in both sending and receiving messages. That renders them capable of serving as a sort of “dimmer switch,” says Conn, dampening or enhancing transmission in specific brain circuits.

Conn and others are looking at compounds that target mGlu receptors as potential antipsychotic therapeutics. “The goal is to screen tens or hundreds of thousands of small molecules to find compounds that have these actions, to develop them to the point where we can show very specific effects on these glutamate circuits, and then test those compounds to see if they have the effect we predicted,” he says.

Conn also is investigating the role of another neurotransmitter, acetylcholine, in schizophrenia.

Some compounds that target specific cholinergic receptors, including a drug under development by Eli Lilly and Co. to treat Alzheimer’s disease, have been found to have both cognitive and antipsychotic effects.

“This is, I think, one of the most promising new directions in antipsychotic research,” says Conn, “and it’s probably one you haven’t heard a lot about. But this psychosis-cognition interface is why those compounds may stand out in terms of potential anti-psychotic efficacy.”

Conn, Meltzer and their colleagues, Dr. Junji Ichikawa and Zhu Li, Ph.D., in the Psychiatry Department are investigating whether the improvement of cognition by atypical antipsychotics may be related to their ability to trigger acetylcholine release. If so, the connection could lead to the next generation of “cognitive enhancers,” says Meltzer.

Tracking inherited traits

The best chance at cracking schizophrenia’s mysteries may lie not with the people who have it but with their relatives. A significant percentage of first-degree relatives display schizotypal behavior, exhibiting some number of traits common to the disorder—for example, verbal memory or difficulty tracking objects moving through space—but not the more disabling symptoms.

Rather than look for single genes, some researchers are bundling these traits, which they call endophenotypes, and are tracing their occurrence in families affected by the disorder.

The hope is that whatever genes are controlling these endophenotypic markers may lie in close proximity to a gene, or genes, that directly contributes to schizophrenia’s pathophysiology. A similar strategy proved successful in colon cancer, where it was found that the disease is not inherited, but its endophenotype—the tendency to form polyps—is.

Sohee Park, Ph.D., adjusts a device used in a new non-invasive technique called near infrared optical imaging that she uses in her studies of cognitive function. As research subject Mikisha Doop takes a computerized working memory test, her brain activity will be monitored through the cap-like device and recorded by a second computer.

Photo by Anne Rayner

Three large genetic studies of schizophrenia are already in the works. Two of the studies were launched in 2002 by researchers at the University of Pennsylvania and the University of Pittsburgh. One plans to enroll 150 families, each of which has at least two affected members. The other—the Project Among African Americans to Explore Risks for Schizophrenia—will be a larger study of families in which two siblings have the disorder. The studies will test for attention, working memory, and executive functions, such as organization, problem solving, and decision-making.

The third study, which began this year, is the effort of the seven-center Consortium on the Genetics of Schizophrenia (COGS), led by the University of California, San Diego. The five-year study will use both cognitive and neurophysiological tests to track six characteristic traits in more than 2,000 individuals, all schizophrenia patients or first-degree relatives.

Knowing the genes at the root of schizophrenia will be useful for designing targeted therapeutics, and may allow for early pharmacological intervention. It may even point the way to future gene therapy.

Yet when heading down such a path, we may want to tread lightly, suggests Park, whose lab is also exploring creative thought as an adaptive reason that the disorder is still in our midst.

“Once we identify a gene or genes, who’s to say they might not also be responsible for divergent thinking and creativity,” she says. “If we turn these genes off, are we going to remove those traits from the human race?”